Research Papers:

Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade

Kei Ishibashi, Tobias Haber, Ines Breuksch, Susanne Gebhard, Takashi Sugino, Hitoshi Kubo, Junya Hata, Tomoyuki Koguchi, Michihiro Yabe, Masao Kataoka, Soichiro Ogawa, Hiroyuki Hiraki, Tomohiko Yanagida, Nobuhiro Haga, Joachim W. Thüroff, Dirk Prawitt, Walburgis Brenner _ and Yoshiyuki Kojima

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Oncotarget. 2017; 8:55230-55245. https://doi.org/10.18632/oncotarget.19420

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Kei Ishibashi1,2, Tobias Haber2, Ines Breuksch3, Susanne Gebhard3, Takashi Sugino4, Hitoshi Kubo5, Junya Hata1, Tomoyuki Koguchi1, Michihiro Yabe1, Masao Kataoka1, Soichiro Ogawa1, Hiroyuki Hiraki1, Tomohiko Yanagida1, Nobuhiro Haga1, Joachim W. Thüroff2, Dirk Prawitt6,*, Walburgis Brenner2,3,* and Yoshiyuki Kojima1,*

1Department of Urology, Fukushima Medical University, Fukushima, Japan

2Department of Urology, Johannes Gutenberg University Medical Center, Mainz, Germany

3Department of Gynecology and Obstetrics, Johannes Gutenberg University Medical Center, Mainz, Germany

4Department of Pathology, Shizuoka Cancer Center, Shizuoka, Japan

5Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan

6Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany

*These authors contributed equally to this work

Correspondence to:

Walburgis Brenner, email: [email protected]

Kei Ishibashi, email: [email protected]

Keywords: renal cell carcinoma, tyrosine kinase inhibitor, resistance, IL-6, tocilizumab

Received: March 01, 2017     Accepted: July 12, 2017     Published: July 21, 2017


Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis.

Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.

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